Analgesics of the Future: Inside the Potential of Nerve Growth Factor Antagonists

Overview

New insights into the pathophysiology of pain have given rise to novel targets for addressing chronic pain. Advancements in clinical research on the role of nerve growth factors (NGFs) in pain conditions has led to the development of anti-NGF monoclonal antibodies (mAbs) that have the potential to specifically target pain at the cellular transcriptional level. Studies have shown that NGF protein expression is typically increased at sites of inflammation and we now understand it plays a role in nociceptor sensitization.1,2 NGF is a neutrophin with a high binding affinity to the tropomyosin-related kinase (trk) family of receptors and low-binding affinity to p75 receptors, both playing important roles in the growth and function of sensory neurons.1-4 The binding of NGF to trk-A in particular, activates the downstream expression of key proteins involved in pain sensitization. By preventing NGF binding to TrKA and p75, mAbs can inhibit downstream signaling pathways that lead to pain-related hypersensitivity.1,3-4

The first humanized immunoglobulin G2 NGF antibody to be developed was tanezumab by Pfizer and Eli Lilly and Company. Being the first of its kind, much of the data on NGF antagonists may be attributed to the tanezumab clinical trials and it has since been studied in several chronic pain states including: hip and knee osteoarthritis (OA), chronic low back pain, cancer pain related to bone metastases, cystitis, and others.4,5 Tanezumab not only has a high affinity for NGF, but it also is highly selective, with an estimated 1,000-fold decrease in affinity for other receptors in the neutrophin family.5 Tanezumab may be administered intravenously or subcutaneously and is currently being studied at doses of 2.5mg and 5mg every 8 weeks.

Fasinumab, developed by Teva Pharmaceutical Industries and Regeneron Pharmaceuticals, is another NGF antibody in development, with clinical trials primarily involving OA of the hip or knee and chronic low back pain.6 Data from early clinical trials of a third biologic, fulranumab by Johnson & Johnson is also available, however, further development of this drug has been discontinued.

Despite promising results in early clinical trials, the FDA placed its first clinical hold on further development and research of all NGF antibodies due to significant safety concerns for study participants in treatment arms developing rapidly progressing osteoarthritis (RPOA).4,6 It should be noted that tanezumab was the only NGF antagonist at this time to be at the advanced stages of development.6 The agency placed a second clinical hold in 2012 due to sympathetic nervous system concerns.6

Clinical trials for tanezumab and fasinumab resumed after the FDA lifted its clinical hold on NGF antagonists in 2015. Of note, tanezumab received a Fast Track designation in July 2017 for the treatment of OA and chronic low back pain.8 Phase 3 trials for tanezumab in OA of the hip or knee and chronic low back pain concluded in November 2018 and December 2018, respectively,9,10 with Phase 3 trials for tanezumab in cancer pain due to bone metastases underway.11 Long-term safety and efficacy studies for both tanezumab and fasinumab are also underway.12,13

The Data

Since the development of NGF antagonists, several multi-center, randomized controlled trials have been completed with promising results. It is important to note that the most robust data in the literature available involve tanezumab, with a majority of the literature based on data obtained from trials completed prior to the FDA clinical hold. A titration dosing study of subcutaneous tanezumab in OA of the hip or knee concluded in May 2018, with results summarized next.

Previous Phase 3 trials of anti-NGF antibodies demonstrated efficacy in the treatment of osteoarthritis. A systematic review by Schnizter and Marks assessed 13 high quality randomized-controlled trials of tanezumab, fulranumab, and fasinumab in OA treatment.14 The analysis demonstrated the superiority of NGF inhibitors compared to placebo as well as active comparators including oral NSAIDs (naproxen) and oxycodone (10 to 40 mg).

Consistent with previous placebo-controlled trials, anti-NGF antibodies continue to demonstrate benefit in osteoarthritis. The titration dosing study of tanezumab was a Phase 3 randomized, double-blinded, placebo-controlled, multicenter, parallel-group, 40-week study that examined the efficacy and safety of subcutaneous tanezumab in hip or knee osteoarthritis.14 Patients with a confirmed diagnosis of osteoarthritis of the knee or hip who failed or did not tolerate acetaminophen, NSAIDs, and tramadol or opioids were enrolled in the study. Each participant also had a baseline (Western Ontario and McMaster Universities Osteoarthritis Index, or WOMAC) Pain and Physical Function score of ≥ 5 (11-point numerical rating scale) and a baseline Patient’s Global Assessment of OA (PGA-OA) of “fair,” “poor,” or “very poor.” Study participants that met inclusion criteria (n = 696) were randomized into three groups: placebo, fixed-dosing, and step-up dosing. Patients in the fixed-dosing group received 2.5mg SC on Day 1 and Week 8 (n = 231) while those in the step-up dosing group received 2 mg SC on Day 1 and 5 mg SC on Week 8 (n = 233). The treatment period concluded at 16 weeks with an additional 24-week safety follow-up.15,16

The primary outcomes were a change from baseline to week 16 in the WOMAC Pain subscale, WOMAC Physical Function subscale, and PGA-OA. Safety measures included adverse event reporting, physical and neurological examinations, joint X-rays, electrocardiogram, and laboratory.14,15 At the end of the treatment period, patients in both treatment groups noted statistically significant improvements in all primary outcome measures compared to placebo (see Table I). Common adverse events included arthralgias, nasopharyngitis, and paresthesias, with one patient in the step-up dosing group discontinuing treatment due to adverse events. Overall, five patients withdrew from the study due to adverse events: two in the placebo group, one in the 2.5mg group, and two in the step-up dosing group. With regard to serious adverse events, RPOA occurred in 1.3% of participants who received tanezumab.15

In April 2019, Pfizer and Eli Lilly announced the results from their Phase 3 long-term safety and efficacy study in hip and knee OA, comparing tanezumab 2.5 mg every 8 weeks, tanezumab 5 mg every 8 weeks, and either naproxen 500 mg, celecoxib 100 mg, or diclofenac XR 75 mg twice daily. The study duration included a 56-week treatment period followed by a 24-week safety follow-up. The study utilized the same primary endpoints as the titration study mentioned previously, however, had mixed results. At Week 16, only two of the three primary endpoints showed statistical significance in the 5 mg group—the WOMAC Pain and Physical Functions subscales— while no primary efficacy endpoints were met in the 2.5mg group. With regards to safety endpoints, the overall incidence of RPOA was 6.3%, 3.2%, and 1.2% in the 5 mg, 2.5 mg, and NSAID arms, respectively.

Not to be outpaced, Teva and Regeneron announced that, at Week 16, their monoclonal antibody has met all primary and key secondary endpoints (see Table II) in a Phase 3 study of fasinumab in the treatment of knee or hip osteoarthritis.17 The randomized, double-blind, placebo-controlled Phase 3 study is a sub-study of a larger trial assessing the long-term safety and tolerability of fasinumab 1 mg every 4 or 8 weeks during an active treatment period of 52 weeks with a 20-week safety follow-up.14 Treatment discontinuation related to adverse events occurred in 5% of patients in the fasinumab every 8 weeks group and 6% in the every 4 weeks group, compared to 6% in the placebo group. So far, the placebo-adjusted rate of arthropathies was about 2%, a majority of which involved RPOA.17

The data available for the use of NGF inhibitors in chronic low back pain is less robust in comparison. As mentioned previously, a Phase 3 trial of tanezumab for chronic low back pain recently concluded. Previous Phase 3 trials, however, demonstrated significant improvements from baseline scores compared to both naproxen and placebo. Of note, only treatment groups receiving 10 mg or 20 mg every 8 weeks showed significant improvement, while results for patients in the 5-mg treatment group were similar to naproxen and placebo.6

Discussion

Despite the promising results, there remains significant safety consideration for the clinical application of anti-NGF monoclonal antibodies. The FDA’s first hold that halted development in 2010 was implemented due to reports of serious joint-related adverse events (AEs), including osteonecrosis, rapidly progressive osteoarthritis (RPOA), while others required total joint replacement (TJR) surgeries.18 Subjects reported 437 serious joint-related AEs in the tanezumab trials, with knees being the most commonly affected (n = 259) followed by hips (n = 157). Increased risk for developing these AEs was associated with higher doses of tanezumab
(>10mg), concomitant NSAID therapy, and in patients with pre-existing fractures.6 Similar cases of TJR were identified in study participants in the fasinumab and fulranumab trials.6

The data available from current clinical trials to date have consistently shown that NGF inhibitors may significantly improve pain and physical function in hip and knee osteoarthritis. Their novel ability to target pain at the level of protein expression makes nerve growth factor inhibitors one of the more unique products in development for chronic pain management. With the limited number of medication options currently available to practitioners due to contraindications for use, intolerance, or abuse potential, NGF inhibitors may prove to be of extreme benefit, especially in patients with OA who are unable to tolerate or have a contraindication to traditional oral NSAIDs. The infrequent dosing requirements (ie, every 8 weeks in most trials), also make these agents an intriguing treatment option, especially in patients at high risk for abusing or misusing their daily oral medications.

Results from both recent and previous clinical trials for NGF antagonists do show promise, however, practitioners should consider several safety concerns, which may limit their use to a very specific patient population. Due to dose-related serious AEs from previous clinical trials, current studies are restricted to lower doses of tanezumab (2.5 mg and 5 mg). The increased risk of joint-related AEs in patients taking NSAIDs concomitantly may further limit its clinical application due to the wide availability of over-the-counter anti-inflammatory products. The risks and benefits should be strongly considered should these biologics become available, especially with the lack of long-term safety and efficacy data. Despite these concerns, the possible benefits of these agents, especially in inflammatory pain conditions, make them a highly anticipated addition for chronic pain management.

PPM Editors-at-Large Weigh In on NGF Inhibiting Potential

One can always say that analgesics of the future are “closer than ever,” but this time we really mean it. It is an exciting time for analgesic pharmaceutical development. Nanotechnologies, delivery systems, and new chemical and biological entities with novel mechanisms of action are all progressing with the goal of finding an optimal analgesic: one with maximum effectiveness and minimum adverse effect.

This month’s highlight is on a molecule that we have been waiting for more than a decade to see: nerve growth factor (NGF) inhibitors. NGF influences both neuronal cell function and immune cell activity and is enhanced during the peripheral and central inflammatory response. As clinicians on the front line, we were hopeful that the preclinical data supporting a remarkable benefit on multiple types of pain would have translated to a successful Phase 3 program leading to eventual approval for osteoarthritis, low back pain, and perhaps even refractory neuropathic pain. As the authors note in the main review herein, despite promising results, significant safety concerns arose during clinical trials. If more than one NGF inhibitor is approved, clinicians will need guidance on optimal patient selection, drug and dose selection, and strategies to optimize therapy while avoiding adverse effects.

Hopefully researchers can build on existing current knowledge of this science and create a next-generation neuronal inflammatory mediator with an improved safety profile. For now, we must continue to support industry and research to fight the war on pain with the rational, multimodal weapons, including opioids in select responsive patients with refractory conditions.

Despite a great report by the authors, because of safety concerns, we give the NGFs in development 3.5 out of 5 stars.

Pfizer. Phase 3 Study on the dfficacy and safety of tanezumab in patients with cancer pain due to bone metastasis who are taking background opioid Therapy. ClinicalTrials.gov (Identifier: NCT02609828). November 20, 2015.

Pfizer. Long term safety and efficacy study of tanezumab in subjects with osteoarthritis of the hip or knee. ClinicalTrials.gov (Identifier: NCT02528188). First posted August 19, 2015.

Regeneron Pharmaceuticals. A phase 3 randomized, double-blind, multi-dose, placebo-controlled study to evaluate the long-term safety and the efficacy of fasinumab in Patients With Pain Due to Osteoarthritis of the Knee or Hip. ClinicalTrials.gov (Identifier: NCT02683239). February 17, 2016.

Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage. 2015;23 Suppl 1:S8-17.

Pfizer. Efficacy and safety of a subcutaneous tanezumab titration dosing regimen in subjects with moderate to severe osteoarthritis of the hip or knee. ClinicalTrials.gov (Identifier: NCT02637773). March 3, 2016.

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